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Exposure to urban air pollutants such as ozone (O₃) is increasingly linked with Alzheimer’s disease; yet because ozone cannot travel from the lungs to the brain, the mechanism by which it contributes to development of Alzheimer’s has been poorly understood. The hypothesis is that an immune response in the lungs leads to downstream changes in gene expression in brain cells. In a mouse model of Alzheimer’s disease, mice exposed to high levels of ozone over time showed increased levels of the protein HMGB1 in the blood, and their brains showed increases in deposition of disease-associated amyloid plaques, decreases in plaque-associated migroglial cells, and increased expression of genes responsible for neuroinflammation. Further study revealed that HMGB1 in the blood is responsible for regulating the neuroimmune response that mediates development of Alzheimer’s disease. Although there was no confirmation that lung tissue inflammation was involved, this is a key piece in the puzzle demonstrating that the peripheral immune system plays a vital role in the brain’s immune responses and is likely the avenue by which ozone exposure leads to risk factors for Alzheimer’s disease.

Full abstract, to be presented at the , October 22-25, 2022 in Chicago, and published in Annals of Neurology:

Ozone Air Pollution and Alzheimer’s Disease: An Emerging Role for HMGB1 in the Lung-Brain Axis

Hendrik J. Greve, PhD, Indiana University School of Medicine

Co-authors: Chandrama Ahmed, BS, MBME, Carla Garza Lombo, PhD, August Dunbar, BS, James A. Johnson, Jr., PhD, Morrent Thang, BS, et al.

An increasing number of epidemiological studies links components of urban air pollution, such as ozone (O₃) with Alzheimer’s disease (AD). However, the mechanisms underlying these associations have remained poorly understood. O₃, a major component of urban air pollution, is unable to pass the respiratory barrier to directly interact with the brain parenchyma due to its reactive chemistry, suggesting an important role for O₃-induced peripheral changes in regulating CNS effects. The lung-brain axis hypothesis posits that inhaled pollutants induce a pulmonary immune response leading to circulating signals which alter brain pathology, particularly AD, but the specific underpinnings of the lung-brain axis are largely unexplored. To begin to address this, 8-10-week-old male 5xFAD mice, a model of AD, were exposed to O₃ (0, 0.3, 1.0 ppm) for 4 hours/day, 3 days/week, for 13 weeks. Analysis of amyloid plaque load in the cortex and hippocampus showed a dose-dependent increase in the number of plaques in the 1.0 ppm O₃-exposed group. Examination of the plaque microenvironment by confocal microscopy showed decreased plaque-associated microglia in O₃-exposed mice with an uncoupling of Trem2 mRNA expression. Further analysis of genes related to neuroinflammation showed increases in Nlrp3 expression in the cortex of O₃-exposed mice. Serum analysis showed increased HMGB1, the canonical damage-associated molecular pattern (DAMP), in 1.0 ppm O₃-exposed mice, without increases in the brain. To further elucidate the role of peripheral HMGB1 in the lung-brain axis, we generated a peripheral myeloid HMGB1 knock out model using a cre-lox system, which has knockdown of HMGB1 in peripheral myeloid populations without knockdown in brain and microglia. Loss of peripheral myeloid HMGB1 rescued O₃-induced changes in Trem2 and Nlrp3 mRNA expression in the brain, but no changes were seen in the pulmonary immune response. Taken together, these data suggest that O₃ exposure exacerbates amyloid pathology, impairs microglia-plaque association, increases neuroinflammation, and increases circulating levels of HMGB1. Further, we found that peripheral myeloid HMGB1 regulates the CNS response to O₃ without increasing the pulmonary response to O₃, suggesting that peripheral myeloid HMGB1 may play important roles in regulating the neuroimmune environment, which has crucial implications for how the peripheral and central immune systems interact and for how air pollution may affect the neurodegenerative process.

All abstracts from ANA2022 will be available in  starting at 3:01 p.m. U.S. Eastern Time on October 14. This research is under embargo until that time. Contact Katherine Pflaumer ([email protected]) for additional highlighted abstracts, full meeting abstracts, and call-in information for the ANA2022 Media Roundtable (Oct. 25, 11 a.m. U.S. Central).

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